ABSTRACT End-stage lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are devastating human conditions for which there are no effective treatments. There is increasing evidence that the inability to maintain epithelial integrity or recovery from sustained injury likely reflects a failure of the stem cell compartment to mount an effective regenerative response. Tissue-specific stem cells are crucial for homeostasis and integrity of adult organs. In the airway epithelium these functions have been attributed largely to multipotent p63-dependent basal cells. However, this role is shared by additional progenitors, particularly by a sizable population of uncommitted p63-negative progenitors which occupy a parabasal location interfacing both basal and luminal differentiating cells. Changes in the size or function of the pool of uncommitted airway epithelial progenitors (basal, parabasal cells) are often accompanied by disruption of the microarchitectural organization seen in hyperplasias and metaplasias of end-stage lung conditions In spite of recent progress, there are still major gaps of knowledge on what collectively the airway endogenous progenitors represent; their origin, diversity, and contribution to plasticity in development, regeneration and disease states. Here we propose to address these gaps of knowledge in our research program to: a) study the molecular and cellular events that control the organization and behavior of the stem cell compartment in the airways, and b) investigate the impact of the disruption of these mechanisms in pulmonary disease pathogenesis. Results from these studies will provide crucial insights currently lacking in the field about how tissue- specific stem cells contribute to normal and disease processes in the lung.